HTRA2 defect: A recognizable inborn error of metabolism with 3-methylglutaconic aciduria as discriminating feature characterized by neonatal movement disorder and epilepsy-report of 11 patients.
Neuropediatrics 49, 373-378 (2018)
Neonatal-onset movement disorders, especially in combination with seizures, are rare and often related to mitochondrial disorders. 3-methylglutaconic aciduria (3-MGA-uria) is a marker for mitochondria) dysfunction. In particular, consistently elevated urinary excretion of 3-methylglutaconic acid is the hallmark of a small but growing group of inborn errors of metabolism (IEM) due to defective phospholipid remodeling or mitochondrial membrane-associated disorders (mutations in TAZ, SERAC1, OPA3, CLPB, DNAJC19, TMEM70, TIMM50). Exome/genome sequencing is a powerful tool for the diagnosis of the clinically and genetically heterogeneous mitochondrial disorders. Here, we report 11 individuals, of whom 2 are previously unpublished, with biallelic variants in high temperature requirement protein A2 (HTRA2) encoding a mitochondria-localized serine protease. All individuals presented a recognizable phenotype with neonatal- or infantile-onset neurodegeneration and death within the first month of life. Hallmark features were central hypopnea/apnea leading to respiratory insufficiency, seizures, neutropenia, 3-MGA-uria, tonus dysregulation, and dysphagia. Tremor, jitteriness, dystonia, and/or clonus were also common. HTRA2 defect should be grouped under the IEM with 3-MGA-uria as discriminating feature. Clinical characteristics overlap with other disorders of this group suggesting a common underlying pathomechanism. Urinary organic acid analysis is a noninvasive and inexpensive test that can guide further genetic testing in children with suggestive clinical findings.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mitochondrial Dysfunction ; Developmental Delay ; Respiratory Insufficiency ; Dystonia ; Tremor; Serine-protease Htra2/omi; Parkinsons-disease; Essential Tremor; Mutations; Deficiency; Omi/htra2; P.g399s; Mice
ISSN (print) / ISBN 0174-304X
Quellenangaben Band: 49, Heft: 6, Seiten: 373-378
Verlag Georg Thieme Verlag
Verlagsort Rudigerstr 14, D-70469 Stuttgart, Germany
Institut(e) Institute of Human Genetics (IHG)